EP0344880B1 - Compositions pharmaceutiques à activité anticancéreuse - Google Patents

Compositions pharmaceutiques à activité anticancéreuse Download PDF

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Publication number
EP0344880B1
EP0344880B1 EP89301763A EP89301763A EP0344880B1 EP 0344880 B1 EP0344880 B1 EP 0344880B1 EP 89301763 A EP89301763 A EP 89301763A EP 89301763 A EP89301763 A EP 89301763A EP 0344880 B1 EP0344880 B1 EP 0344880B1
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EP
European Patent Office
Prior art keywords
cisplatin
benzylidene
cells
pharmaceutical composition
bass
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP89301763A
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German (de)
English (en)
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EP0344880A3 (en
EP0344880A2 (fr
Inventor
Reidar Oftebro
Erik Pettersen
John Michael Dornish
Bernt Borretzen
Rolf Olav Larsen
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Norsk Hydro ASA
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Norsk Hydro ASA
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Priority to AT89301763T priority Critical patent/ATE79757T1/de
Publication of EP0344880A2 publication Critical patent/EP0344880A2/fr
Publication of EP0344880A3 publication Critical patent/EP0344880A3/en
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Publication of EP0344880B1 publication Critical patent/EP0344880B1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to pharmaceutical compositions which have activity as anti-cancer agents and to methods for the treatment of cancer in patients.
  • Cisplatin or cis-dichlorodiammineplatinum-II, has been used successfully for many years as a chemotherapeutic agent in the treatment of various human solid malignant tumours.
  • Cisplatin has the structural formula: More recently, other diamino-platinum complexes have also been proposed for use as anti-cancer drugs, for example spiro-platinum and carbo-platinum.
  • cisplatin Although cisplatin is widely used in medicine, nonetheless it is not therapeutically effective in all patients, nor against all types of solid malignant tumours. Moreover, it has to be administered at high dosage levels such as can cause kidney damage unless special precautions are taken.
  • anti-cancer platinum complexes such as cisplatin unexpectedly exhibit a higher level of anti-tumour activity, as demonstrated by an in-vitro model, if administered substantially simultaneously with 5,6-O-benzylidene-L-ascorbic acid (hereafter sometimes abbreviated as BASS).
  • BASS 5,6-O-benzylidene-L-ascorbic acid
  • BASS is disclosed in the literature as possessing anti-cancer properties, we have found that the enhancement of cytotoxic activity on human cancer cells which is exhibited when this substance is administered in conjunction with anti-cancer platinum complexes such as cisplatin is synergistic and not merely additive. This result is highly surprising, more especially since one effect of the co-administration of an anti-cancer platinum complex such as cisplatin with BASS is to reduce the up-take of platinum by the malignant cells, whereas the prior work on cisplatin in particular has taught that an increase in the platinum take-up increases the toxicity of cisplatin.
  • the 5,6-O-benzylidene-L-ascorbic acid (ie BASS) can be used herein either as the free acid or in the form of its salts with pharmaceutically acceptable cations.
  • the 5,6-O-benzylidene-L-ascorbic acid may be deuterated at the 1-position of the benzylidene moiety; other work which we have done suggests that such deuterated BASS may have advantages in anti-cancer therapy over non-deuterated BASS.
  • the present invention provides a pharmaceutical composition useful as an anti-cancer agent, comprising as active ingredients:
  • the present invention also encompasses the use of a compound selected from 5,6-O-benzylidene-L-ascorbic acid, 5,6-O-benzylidene-L-ascorbic acid deuterated at the 1-position of the aldehyde group and pharmaceutically acceptable salts of said acids, for the manufacture of a medicament for use in a platinum complex anti-cancer therapy.
  • deuterated 5,6-O-benzylidene-L-ascorbic acid useful herein may additionally be partially or completely deuterated at other positions of its molecular structure, ie in addition to the deuterium atom at the 1-position of the aldehyde group of the benzylidene moiety, one or more hydrogen atoms in the structure may be replaced by deuterium atoms.
  • the pharmaceutical composition of this invention preferably comprises a freeze-dried mixture of the active ingredients in a unit dosage form ready for make-up with Water for Injection or other suitable infusion liquid.
  • the freeze-dried compositions of this invention may also include sodium chloride (to provide the required isotonicity to the infusion liquid), and/or mannitol (to help protect against kidney damage.
  • Synchronized cell populations with a high degree of synchrony were obtained by repeated selection of mitotic cells (Pettersen, E.O. et al, Cell Tissue Kinet., 10: 511-522, 1977). During the synchronization procedure, the cells were kept in Medium E2a, and the whole experiment took place in a walk-in incubator at 37°C. Under growth conditions as used here, the NHIK 3025 cells have a medium cell-cycle time of ⁇ 18 h, with medium G1, S1 and G2 durations of ⁇ 7, ⁇ 8, and ⁇ 2.5 h, respectively.
  • the cells within a delineated area of the flask were observed repeatedly in an inverted microscope, and the time of entrance into mitosis, as well as the time of division, were noted for each separate cell. Analyses of durations of mitosis were performed from these observations (Table).
  • the cells were centrifuged and washed in phosphate-buffered NaCl solution (NaCl, 8000 mg/liter; Na2HPO4.2H2O, 1150 mg/liter; KH2PO4, 200 mg/liter; KCl, 200 mg/liter).
  • the cell pellet was taken up into 100 ⁇ l concentrated HNO3.
  • 100 ⁇ l H2O was then added to each tube.
  • Aliquots of 25 ⁇ l (representing 250,000 cells) were then placed in a graphite tube and the atomic absorption signal measured at 265.9 nm was registered. Platinum content was quantitated by running a calibration curve immediately before the samples.
  • This experiment measured the fraction of NHIK 3025 cells surviving a 2 hour treatment with a combination of 3 ⁇ M cisplatin and BASS at various concentrations. The results are given in Table 2. The values given in the Table represent cell survival after the treatment with drug combination relative to that after treatment with 3 ⁇ m cisplatin alone.
  • Table 2 shows relative survival values ie relative to cisplatin alone, ie any potentiation of cisplatin toxicity by BASS would thus reduce the relative survival values to below 1.0. From Table 2, it will be seen that the potentiating effect of BASS was most apparent at concentrations above 0.5 mM.
  • This experiment measured the prolongation of the median cell-cycle duration of synchronized cells treated with either 1.5 ⁇ M of cisplatin or 2.0 mM of BASS alone, or with the two active ingredients in simultaneous combination.
  • This experiment measured, by means of atomic absorption spectroscopy, the amount of cell-associated platinum following 2 hour treatment with 30 ⁇ m cisplatin alone, or 2 hour simultaneous treatment with the combination of 30 ⁇ M cisplatin and BASS.
  • the results are given in Table 6, and in which the values given represent the amount of cell associated platinum after the combined treatment relative to that after treatment with cisplatin alone.
  • Table 6 shows that BASS reduces the relative amount of cisplatin in cells.
  • the two active ingredients may be formulated together in a pharmaceutical composition for simultaneous intravenous injection, or alternatively each active ingredient may be administered separately, provided that the patient receives the correct dosage of each active ingredient substantially simultaneously to ensure that the synergistic effect is manifested in the patient.
  • the BASS-or may be given either orally to immediately precede, or simultaneously with, cisplatin administration.
  • cisplatin administration 56-O-benzylidene-L-ascorbic acid or salt thereof, or of a deuterated aldehyde derivative, will be in the range of 10 to 75 mg per kg body weight up to twice daily, with the anti-cancer platinum compound being given during one of the BASS treatment periods.
  • BASS or an acceptable salt thereof may be given simultaneously with but independently of the platinum treatment, or simultaneously with and in admixture with the anti-cancer platinum compound.
  • the suitable ranges for 5,6-O-benzylidene-L-ascorbic acid or alkaline earth salts thereof, or of the deuterated compounds will be 10 to 75 mg per kg body weight up to twice daily with the anti-cancer platinum compound being administered during one of the BASS treatment periods.
  • the dosage of cisplatin or other platinum complex is suitably within the range of 0.5 to 2 mg per kg body weight for cisplatin, or from 0.5 to 50 mg per kg body weight for other anti-cancer platinum compounds, for example carboplatinum, either once every 3-4 weeks as a single dose, or daily from 1 to 5 days as split dosages such that the total platinum dosage does not exceed the above ranges.
  • 0.15 g to 1.5 g of BASS will preferably be given orally per day in combination with up to 150 mg of cisplatin intravenously.
  • an adult patient preferably would receive 0.15 g to 1.5 g of BASS, either in combination with 50 to 150 mg of cisplatin or singly, in the latter case the cisplatin then also being given singly but substantially simultaneously.
  • compositions containing both the active ingredients of the present invention for intravenous infusion or injection may be-formulated in numerous ways well known to those skilled in the art with pharmaceutically acceptable excipients or carriers for injection or infusion.
  • freeze-dried mixtures of the active ingredients in a unit dosage form, prepared by conventional methods preferably are made up with Water for Injection or other suitable infusion liquid at the time of administration.
  • the content of the active ingredients in the pharmaceutical compositions according to this invention may vary quite widely, depending on the required dosage.
  • the content of 5,6-O-benzylidene-L-ascorbic acid or pharmaceutically acceptable salt thereof will usually be 10:1 to 1000:1 by weight, with respect to the anti-cancer platinum complex present in the composition.
  • Corresponding amounts will apply for the deuterated BASS compounds.
  • the compositions will comprise from 5 mg to 500 mg of the anti-cancer platinum complex, and from 100 mg to 10,000 mg of the ascorbate.
  • Mannitol and/or sodium chloride may preferably be included in amounts conventional for cisplatin preparations.
  • Physiological pH of injectables or infusion drug combinations will be established by inclusion of buffering agents as is known in the pharmaceutical art.
  • compositions containing these active ingredients may be presented in the form of tablets, capsules, granules or powders, in accordance with procedures known in the pharmaceutical formulation art.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (8)

  1. Composition pharmaceutique, pouvant utilement servir d'agent anti-cancer,comprenant, comme ingrédients actifs :
    (i) un complexe de platine à rôle anti-cancer ; et
    (ii) un composé choisi parmi l'acide 5,6-O-benzylidène-L-ascorbique, l'acide 5,6-O-benzylidène-L-ascorbique deutéré au moins sur la position 1 du groupe aldéhyde du fragment benzylidène, et les sels pharmaceutiquement acceptables desdits acides.
  2. Composition pharmaceutique selon la revendication 1, dans laquelle ledit ingrédient actif est le cisplatine.
  3. Composition pharmaceutique selon la revendication 1 ou la revendication 2, dans laquelle ledit ingrédient actif (ii) est ou comprend le composé de formule
    Figure imgb0010
     dans laquelle X représente un atome d'hydrogène ou un cation de métal pharmaceutiquement acceptable.
  4. Composition pharmaceutique selon l'une quelconque des revendications précédentes, dans laquelle lesdits sels pharmaceutiquement acceptables sont choisis parmi des sels de métaux alcalins et des sels de métaux alcalino-terreux.
  5. Composition pharmaceutique selon l'une quelconque des revendications précédentes, comprenant un mélange desdits ingrédients actifs (i) et (ii) sous forme lyophilisée.
  6. Composition pharmaceutique selon la revendication 5, comprenant de 5 mg à 500 mg en poids dudit ingrédient actif (i) et de 100 mg à 10 000 mg dudit ingrédient actif (ii).
  7. Composition pharmaceutique selon la revendication 5 ou la revendication 6, comprenant également du mannitol et du chlorure de sodium.
  8. Utilisation d'un composé choisi parmi l'acide 5,6-O-benzylidène-L-ascorbique, l'acide 5,6-O-benzylidène-L-ascorbique deutéré au moins sur la position 1 du groupe aldéhyde du fragment benzylidène, et leurs sels pharmaceutiquement acceptables, pour la fabrication d'un médicament destiné à servir dans un traitement anti-cancer utilisant un complexe du platine.
EP89301763A 1988-04-29 1989-02-23 Compositions pharmaceutiques à activité anticancéreuse Expired - Lifetime EP0344880B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT89301763T ATE79757T1 (de) 1988-04-29 1989-02-23 Pharmazeutische zusammensetzungen mit krebshemmender wirkung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8810173 1988-04-29
GB888810173A GB8810173D0 (en) 1988-04-29 1988-04-29 Pharmaceutical compositions with anti-cancer activity & method for treatment of cancer

Publications (3)

Publication Number Publication Date
EP0344880A2 EP0344880A2 (fr) 1989-12-06
EP0344880A3 EP0344880A3 (en) 1990-04-18
EP0344880B1 true EP0344880B1 (fr) 1992-08-26

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EP89301763A Expired - Lifetime EP0344880B1 (fr) 1988-04-29 1989-02-23 Compositions pharmaceutiques à activité anticancéreuse

Country Status (11)

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US (2) US5049396A (fr)
EP (1) EP0344880B1 (fr)
JP (1) JPH0296524A (fr)
AT (1) ATE79757T1 (fr)
AU (1) AU618997B2 (fr)
CA (1) CA1326441C (fr)
DE (1) DE68902581T2 (fr)
DK (1) DK207889A (fr)
ES (1) ES2051997T3 (fr)
GB (1) GB8810173D0 (fr)
GR (1) GR3006004T3 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9026114D0 (en) * 1990-11-30 1991-01-16 Norsk Hydro As New compounds
JPH06192109A (ja) * 1992-09-04 1994-07-12 Fuji Kagaku Kogyo Kk 抗腫瘍効果増強剤
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO1995026325A2 (fr) * 1994-03-25 1995-10-05 Isotechnika Inc. Potentialisation de medicaments par deuteration_______________
US5955498A (en) * 1994-04-27 1999-09-21 Tanuma; Sei-Ichi Agent for prophylaxis and therapy of diseases
JP2990015B2 (ja) * 1994-06-20 1999-12-13 睦之 東風 抗ｈｉｖ剤
DE4427690A1 (de) * 1994-08-04 1996-02-08 Bogdahn Ulrich Prof Deuterium enthaltende pharmazeutische Zusammensetzung als Zytostatikum oder Tumor-Therapeutikum
US5639787A (en) * 1995-02-28 1997-06-17 The Center For The Improvement Of Human Functioning Int'l, Inc. Therapeutic method for the treatment of cancer
EP1002535A1 (fr) * 1998-10-28 2000-05-24 Hrissanthi Ikonomidou Nouvelle utilisation des antagonistes du glutamate pour le traitement du cancer
EP2289549A3 (fr) 1999-10-01 2011-06-15 Immunogen, Inc. Des immunoconjugués pour le traitement des cancers.
US6573050B1 (en) 1999-10-29 2003-06-03 Sunnybrook & Women's College Health Sciences Centre Treatment, diagnosis and evaluation of anti-cancer therapy resistance in melanoma
AUPQ641100A0 (en) * 2000-03-23 2000-04-15 Australia Nuclear Science & Technology Organisation Methods of synthesis and use of radiolabelled platinum chemotherapeutic ag ents
US6468980B1 (en) * 2000-09-01 2002-10-22 Oxycal Laboratories, Inc. Methods and compositions for potentiating cancer chemotherapeutic agents
US20050220899A1 (en) * 2002-05-07 2005-10-06 Clet Niyikiza Use of cisplatin in combination with folic acid for increasing cisplatin efficacy
US20060275504A1 (en) * 2005-06-07 2006-12-07 Tty Biopharm Company Limited Methods and compositions for augmenting cancer chemotherapeutic agents
WO2012013229A1 (fr) * 2010-07-28 2012-02-02 Fondazione Irccs Agent thérapeutique, composition comprenant ledit agent, dispositif implantable et procédé pour le traitement du cancer du col de l'utérus et/ou pour la prévention de la formation de néoplasmes en correspondance avec le col de l'utérus dans un système génital féminin humain
US20140065096A1 (en) * 2012-09-05 2014-03-06 Regen BioPharma, Inc. Cancer therapy by ex vivo activated autologous immune cells

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4457926A (en) * 1979-06-20 1984-07-03 Engelhard Corporation Cis-Platinum(II) amine ascorbate complexes
JPS60139619A (ja) * 1983-12-27 1985-07-24 Mutsuyuki Kochi Ｏ−ベンジリデン−アスコルビン酸又はその塩よりなる抗腫瘍剤

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ES2051997T3 (es) 1994-07-01
AU3245489A (en) 1989-11-02
US5130145A (en) 1992-07-14
GR3006004T3 (fr) 1993-06-21
JPH0296524A (ja) 1990-04-09
DE68902581D1 (de) 1992-10-01
DK207889A (da) 1989-10-30
AU618997B2 (en) 1992-01-16
CA1326441C (fr) 1994-01-25
DE68902581T2 (de) 1992-12-24
DK207889D0 (da) 1989-04-28
GB8810173D0 (en) 1988-06-02
EP0344880A3 (en) 1990-04-18
US5049396A (en) 1991-09-17
EP0344880A2 (fr) 1989-12-06
ATE79757T1 (de) 1992-09-15

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